EP0677043A1 - Composes inhibant l'aggregation des plaquettes - Google Patents

Composes inhibant l'aggregation des plaquettes

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Publication number
EP0677043A1
EP0677043A1 EP94905502A EP94905502A EP0677043A1 EP 0677043 A1 EP0677043 A1 EP 0677043A1 EP 94905502 A EP94905502 A EP 94905502A EP 94905502 A EP94905502 A EP 94905502A EP 0677043 A1 EP0677043 A1 EP 0677043A1
Authority
EP
European Patent Office
Prior art keywords
compound according
methyl
mmol
4alkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP94905502A
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German (de)
English (en)
Other versions
EP0677043A4 (fr
Inventor
William Edward Bondinell
James Francis Callahan
William Francis Huffman
Richard Mcculloch Keenan
Brian Walter Metcalf
James Samanen
Tobias Oregon Yellin
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0677043A1 publication Critical patent/EP0677043A1/fr
Publication of EP0677043A4 publication Critical patent/EP0677043A4/xx
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • a nitrogen heterocycle which may be a saturated or an unsaturated stable five-, six- or seven-membered monocychc ring or a seven- to ten- membered bicyclic ring, containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure, and wherein the nitrogen heteroatom may be optionally quaternized.
  • the nitrogen heterocycle may be substituted in any stable position by C ⁇ _4alkoxy, C ⁇ alkylthio, F, Cl, Br, I, N0 2 , NR' 2 , OH, C0 2 R ⁇ CONHR', or C ⁇ _4alkyl.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t- butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • BrZ refers to the o-bromobenzyloxycarbonyl radical
  • C1Z refers to the o-chlorobenzyloxycarbonyl radical
  • Bzl refers to the benzyl radical
  • 4-MBzl refers to the 4-methyl benzyl radical
  • Me refers to methyl
  • Et refers to ethyl
  • Ac refers to acetyl
  • Alk refers to C]_4alkyl
  • Nph refers to 1- or 2-naphthyl
  • cHex refers to cyclohexyl.
  • MeArg is N ⁇ -methyl
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP refers to dimethylaminopyridine
  • DIEA refers to diisopropylethyl amine
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)carbodiimide.
  • the compounds of formula (I) are generally prepared by reacting a compound of the formula (II) with a compound of the formula (III):
  • L 1 and L 2 are functional groups which are capable of reacting to form the linkage -(CR'R 10 )r-U-(CR' 2 ) s -V-;
  • R6" is W-(CR'2)q-Z- and any portion of the group -(CR'R 10 ) r -U- (CR'2)s-V- which is connected to L 2 , with any reactive functional groups protected; and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
  • L 1 and L 2 will be dependent upon the site of the linkage being formed.
  • General methods for preparing the linkage -(CR'R 10 ) r -U-(CR'2) s -V- are described, for example, in EP-A 0 372 486 and EP-A 0 381 033 and EP-A 0 478 363, which are incorporated herein by reference.
  • L 1 may be -NH2
  • L 2 may be OH (as in an acid) or Cl (as in an acid chloride)
  • R 6" may be W-(CR'2) q -Z- (CR'R 10 )r-tJ-(CR'2)s-C(O), with any functional groups optionally protected.
  • R 6" may be (benzyloxycarbonyl- amidino)benzoyl- or (N ⁇ -Boc,N& uan -Tos)arginyl-.
  • L 2 is OH
  • a coupling agent is used.
  • L* may be -C0 2 H or CO-C1
  • L 2 may be - NH 2
  • R 6" may be W-(CR , 2)q-Z-(CR , R 1 0) r -U-(CR * 2) s -.
  • R6 " may be (benzyloxycarbonyl-amidino)phenyl, (benzyloxycarbonylamino)methylbenzyl- or 6- (benzyloxycarbonylamino)hexyl-.
  • V is NHSO2
  • L 1 may be SO2CI
  • L 2 may be -NH 2 and R 6" may be as above.
  • V is SO2NH
  • L 1 may be -NH2
  • L 2 may be SO2CI.
  • Ll may be -CHO
  • R6 " may be W-(CR ' 2)q-Z-(CR'R l O) r -U-(CR'2) s -.
  • V is CHOHCH2
  • Coupling methods to form peptide bonds are generally well known to the art.
  • the methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique and are incorporated herein by reference.
  • Solution synthesis for the formation of amide or peptide bonds is accomplished using conventional methods used to form amide bonds.
  • the amine or aniline is coupled via its free amino group to an appropriate carboxylic acis substrate using a suitable carbodiimide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
  • DCC N,N' dicyclohexyl carbodiimide
  • catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
  • Other methods such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in the presence of a base, are also suitable.
  • W is a generally a basic functional group attached to Z, optionally via an alkyl chain, and is protected during the synthesis or is introduced into the molecule after the -(CR'R 10 ) r -U-(CR'2) s -V- linkage has been formed.
  • a t-Bu, cHex or benzyl ester may be used for the protection of the side chain carboxyl.
  • a benzyl group or suitably substituted benzyl group eg. 4-methoxy-benzyl or 2,4- dimethoxy-benzyl
  • the tosyl group may be used for protection of the imidazolyl group and tosyl or nitro group for protection of the guanidino group.
  • a suitably substituted carbobenzyloxy group or benzyl group may be also be used for the hydroxyl group or amino group.
  • R' may be prepared by methods disclosed in EP-A 0483 667, which is incorporated herein by reference.
  • (CH 2 ) t -D may be prepared by the methods detailed in EP-A 0319 506, which is incorporated herein by reference.
  • C'R 10 (CR'R 10 ) (A S ) may be prepared by methods disclosed in EP-A 0425 212, which is incorporated herein by reference.
  • Acid addition salts of the compounds of formula (I) are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
  • the acetate salt form is especially useful.
  • Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.
  • This invention provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier. Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution.
  • Suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • Solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non- aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • DIC disseminated intravascular coagulation
  • septicemia surgical or infectious shock
  • post-operative and post-partum trauma cardiopulmonary bypass surgery
  • incompatible blood transfusion abruptio placenta
  • thrombotic thrombocytopenic purpura TTP
  • snake venom and immune diseases
  • the compounds of this invention may be useful in a method for the prevention of metastatic conditions, the prevention or treatment of fungal or bacterial infection, inducing immunostimulation, and the prevention or treatment of diseases in which bone resorption is a factor.
  • the compounds of this invention are administered either orally or parenterally to the patient, in a manner such that the concentration of drug in the plasma is sufficient to inhibit platelet aggregation, or other such indication.
  • the pharmaceutical compositions containing the compounds of this invention are administered at a dose between about 0.2 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • parenteral administration is preferred.
  • an intravenous infusion of the compound in 5% dextrose in water or normal saline is most effective, although an intramuscular bolus injection may be sufficient.
  • oral administration of a capsule or tablet, or a bolus intramuscular injection is suitable.
  • the compounds of this invention are administered one to four times daily at a level of about 0.4 to about 50 mg/kg to achieve a total daily dose of about 0.4 to about 200 mg kg/day.
  • This invention further provides a method for inhibiting the reocclusion of an artery or vein following fibrinolytic therapy, which comprises internal administration of a compound of formula (I) and a fibrinolytic agent. It has been found that administration of certain compounds in fibrinolytic therapy either prevents reocclusion completely or prolongs the time to reocclusion.
  • fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot.
  • Plasminogen activators are a well known group of fibrinolytic agents.
  • Useful plasminogen activators include, for example, anistreplase, urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissue plasminogen activator (tPA) and mutants, or variants, thereof, which retain plasminogen activator activity, such as variants which have been chemically modified or in which one or more amino acids have been added, deleted or substituted or in which one or more or functional domains have been added, deleted or altered such as by combining the active site of one plasminogen activator with the fibrin binding domain of another plasminogen activator or fibrin binding molecule.
  • Other illustrative variants include tPA molecules in which one or more glycosylation sites have been altered.
  • plasminogen activators are variants of tPA in which the primary amino acid sequence has been altered in the growth factor domain so as to increase the serum half-life of the plasminogen activator.
  • tPA Growth factor variants are disclosed, e.g., by Robinson et al., EP-A 0 297 589 and Browne et al., EP- A 0 240 334.
  • Other variants include hybrid proteins, such as those disclosed in EP 0 028 489, EP 0 155 387 and EP 0 297 882, all of which are incorporated herein by reference.
  • Anistreplase is a preferred hybrid protein for use in this invention.
  • Fibrinolytic agents may be isolated from natural sources, but are commonly produced by traditional methods of genetic engineering.
  • the fibrinolytic agent may be formulated in an aqueous, buffered, isotonic solution, such as sodium or ammonium acetate or adipate buffered at pH 3.5 to 5.5. Additional excipients such as polyvinyl pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene, glycol, mannitol and sodium chloride may also be added. Such a composition can be lyophilized.
  • the pharmaceutical composition may be formulated with both the compound of formula (I) and fibrinolytic in the same container, but formulation in different containers is preferred.
  • both agents are provided in solution form they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement. Indications for such therapy include myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and other infarct-related disorders.
  • the compound of this invention is administered just prior to, at the same time as, or just after parenteral administration of tPA or other fibrinolytic agent. It may prove desirable to continue treatment with the claimed compounds for a period of time well after reperfusion has been established to maximally inhibit post-therapy reocclusion.
  • the effective dose of tPA, SK, UK or pUK may be from 0.5 to 5 mg kg and the effective dose of the peptide may be from about 0.1 to 25 mg kg.
  • a kit for convenient administration of the inhibitor and the fibrinolytic agent at the same or different times, comprising, in a single container, such as a box, carton or other container, individual bottles, bags, vials or other containers each having an effective amount of the inhibitor for parenteral administration, as described above, and an effective amount of tPA, or other fibrinolytic agent, for parenteral administration, as described above.
  • kit can comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized plugs, and containers of solutions for reconstitution.
  • a variation of this is to include the solution for reconstitution and the lyophilized plug in two chambers of a single container, which can be caused to admix prior to use.
  • the fibrinolytic and the compound of this invention may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container.
  • both agents When both agents are provided in solution form, they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
  • the platelet aggregation inhibitor may be in an i.v. injectable form, or infusion bag linked in series, via tubing, to the fibrinolytic agent in a second infusion bag.
  • a patient can receive an initial bolus-type injection or infusion of the inhibitor followed by an infusion of the fibrinolytic agent.
  • the pharmacological activity of the compounds of this invention is assessed by their ability to inhibit the binding of 3 H-SK&F 107260, a known RGD-fibrinogen antagonist, to the GPIIblHa receptor; their ability to inhibit platelet aggregation, in vitro, and their ability to inhibit thrombus formation in vivo.
  • GPIIb-IIIa Ten units of outdated, washed human platelets (obtained from Red Cross) were lyzed by gentle stirring in 3% octylglucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl2 at 4°C for 2 h. The lysate was centrifuged at 100,000g for 1 h. The supernatant obtained was applied to a 5 mL lentil lectin sepharose 4B column (E.Y. Labs) preequilibrated with 20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2, 1% octylglucoside (buffer A).
  • the column was washed with 50 mL cold buffer A.
  • the lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C.
  • the GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.
  • the dimethylformamide was removed on a rotovap at 40°C.
  • the residue was partitioned between ethyl acetate and water, and the organic layer rinsed one time with water, two times with 5% citric acid, once again with water, twice with 5% sodium bicarbonate solution, again with water, and finally one time with brine.
  • the organic solution was dried on sodium sulfate, and the ethyl acetate removed. From this solution was recovered 85 mg (55%) of the starting peptide.
  • the combined aqueous rinses were adjusted to pH 9 using dilute NaOH, and extracted with dichloromethane. Chromatography was carried out on the oil thus obtained on silica gel using 5% methanol / methylene chloride.
  • Canavanine sulfate (5.0 g, 18.2 mmol, Sigma) was dissolved in a mixture of 10% NaOH (aqueous, 50 mL) and t-butyl alcohol (50 mL) and was treated with di-t-butyl-dicarbonate (12.0 g, 55 mmol) at room temperature for 13 d. (reaction complete in 2 d.). The reaction mixture was evaporated under vacuum and then evaporated at reduced pressure from methanol. The crude product was stored as its sodium salt under vacuum and used without further purification: MS (FAB) sodium salt: m e 398 [(M-H)+Na]+.
  • the protected canavanine salt from above in DMF 250 mL was treated with diisopropylethylamine (19 mL, 109.3 mmol), methyl glycinate hydrochloride (4.58 g, 36.5 mmol, Schweizerhall), 1- hydroxybenzotriazole (4.93 g, 36.5 mmol) and benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (16.1 g, 36.5 mmol) and stirred at room temperature for 24 h .
  • N ⁇ -t-Butyloxycarbonyl- ⁇ -benzyl-aspartyl-anilide (2.75 g, 6.9 mmol) was treated with 4N HC1 in dioxane at room temperature for 4 h. The reaction mixture was evaporated at reduced pressure. The residue was then evaporated first from toluene and then from toluene/methanol and dried under vacuum to give crude product which was used without further purification.
  • N ⁇ -t-Butyloxycarbonyl-N ⁇ -t-butyloxycarbonyl-canavaninyl-glycinyl- ⁇ -benzyl-aspartyl-anilide Compounds ⁇ -Benzyl-aspartyl-anilide hydrochloride and N ⁇ -t- butyloxycarbonyl-N ⁇ -t-butyloxycarbonyl-canavaninyl-glycine were dissolved in DMF (200 mL) and treated with diisopropylethylamine (3.61 mL, 20.7 mmol), 1-hydroxybenzotriazole (932 mg, 6.9 mmol) and benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (3.05 g, 6.9 mmol) and stirred at room temperature for 5 d.
  • the protected peptide from above was dissolved in methanol with 5% Pd/C and treated with hydrogen (Parr reactor, 50 psi, room temperature) for 4 h.
  • the reaction mixture was filtered through a pad of Celite® and evaporated at reduced pressure. The residue was then evaporated from a mixture of toluene and methanol to give 190 mg of crude product.
  • TLC Rf 0.23 sica gel, 4:1:1 butanol : acetic acid : water
  • TLC Rf 0.42 sica gel, 1:1:1:1 butanol : acetic acid : water : ethyl acetate
  • Example 7(vi) The compound of Example 7(vi) (5.0 g, 5.8 mmol) was dissolved in ethanol (100 mL) with warning. It was treated with 10%palladium on carbon (2.0 g) which had been washed with aqueous acetic acid and filtered. The mixture was shaken in a hydrogen atmosphere for 15 h, filtered and the filtrate was concentrated to yield the title compound (4.4 g, 88%).
  • Example 9(i)(a)(3.1 g, 3.7 mmol) and acetic acid were heated to 50°C and zinc powder (5.6 g) was added in 15 min intervals. The hot mixture was filtered, the filtrate was concentrated and the residue was chromatographed (silica gel, 30% ether/petroleum) to give the title compound (2.2 g, 74%): TLC Rf 0.42 (silica, 7:3 petroleum ether:ether).
  • Example 9(vi) was treated with hydrogen fluoride and anisole to give the title compound.
  • Example 12(viii) The compound of Example 12(viii) was treated with 50% TFA/CH2CI2 as in Example 12(v) to provide the TFA salt of the titled compound.
  • (x) Mba(SEt)MeAmf(cBZ)-Gly-Asp(0-cHex)-Man(4-MBzl)
  • the compound 12(ix) was coupled to Mba(SEt) as in Example 12(vi) to provide the titled compound.
  • Example 12(x) The protected linear peptide of Example 12(x) (0.25 g, 0.25 mmoL), was treated with anhydrous HF (lOmL) and anisole (lmL) at 0 9 C for 1 hr. The HF was removed at 0 9 C under vacuum, and the residue was washed with ether to yield a tan solid (0.116 g).
  • Esgtmplg 1 Parenteral Dosaqre Unit Composition A preparation which contains 20 mg of the compound of Example 4 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions into a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume.
  • D5W dextrose in water
  • Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
  • Example 15 Oral Dosage Unit Composition A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 4 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet.

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Abstract

Composés de la formule (I): W-(CR'2)q-Z-(CR'R10)r-U-(CR'2)s-V-(Gly)n-(Asp)m-A efficaces pour l'inhibition de l'aggrégation des plaquettes, compositions pharmaceutiques présentant une telle activité et procédé d'inhibition de l'aggrégation des plaquettes.
EP94905502A 1992-12-29 1993-12-22 Composes inhibant l'aggregation des plaquettes Ceased EP0677043A1 (fr)

Applications Claiming Priority (3)

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US99963092A 1992-12-29 1992-12-29
US999630 1992-12-29
PCT/US1993/012530 WO1994014775A1 (fr) 1992-12-29 1993-12-22 Composes inhibant l'aggregation des plaquettes

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EP0677043A1 true EP0677043A1 (fr) 1995-10-18
EP0677043A4 EP0677043A4 (fr) 1995-11-22

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EP (1) EP0677043A1 (fr)
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Publication number Priority date Publication date Assignee Title
US5750754A (en) * 1993-03-29 1998-05-12 Zeneca Limited Heterocyclic compounds
WO1994022834A1 (fr) * 1993-03-29 1994-10-13 Zeneca Limited Derives heterocycliques utilises comme inhibiteurs d'agregation plaquettaire
US5753659A (en) * 1993-03-29 1998-05-19 Zeneca Limited Heterocyclic compouds
WO1994022835A2 (fr) * 1993-03-29 1994-10-13 Zeneca Limited Composes heterocycliques en tant qu'inhibiteurs de l'agregation plaquettaire
US5652242A (en) * 1993-03-29 1997-07-29 Zeneca Limited Heterocyclic derivatives
US5977124A (en) * 1995-05-10 1999-11-02 Pfizer Inc. β-adrenergic agonists
CA2220538A1 (fr) * 1995-05-10 1996-11-14 Pfizer Inc. Agonistes du recepteur .beta.-adrenergique
US6008213A (en) * 1995-06-29 1999-12-28 Smithkline Beecham Corporation Integrin receptor antagonists
CA2242877A1 (fr) * 1996-01-16 1997-07-24 Merck & Co., Inc. Antagonistes du recepteur integrine
DE19831710A1 (de) * 1998-07-15 2000-01-20 Merck Patent Gmbh Diacylhydrazinderivate
WO2003059251A2 (fr) 2001-10-22 2003-07-24 The Scripps Research Institute Composes de ciblage d'anticorps
AU2003900608A0 (en) * 2003-02-11 2003-02-27 Fujisawa Pharmaceutical Co., Ltd. Hdac inhibitor
JP4910695B2 (ja) * 2004-02-25 2012-04-04 アステラス製薬株式会社 血栓造影剤
EP1945262A2 (fr) * 2005-10-20 2008-07-23 The Scripps Research Institute Marquage de parties fc pour l'immunocoloration et l'immunociblage
WO2010093706A2 (fr) 2009-02-10 2010-08-19 The Scripps Research Institute Vaccination programmée chimiquement

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EP0381033A1 (fr) * 1989-01-31 1990-08-08 F. Hoffmann-La Roche Ag Amides d'acides carboxyliques et amides sulfoniques
EP0445796A2 (fr) * 1990-03-09 1991-09-11 F. Hoffmann-La Roche Ag Dérivés de l'acide acétique
EP0454651A2 (fr) * 1990-04-23 1991-10-30 Monsanto Company Inhibiteurs de l'aggrégation plaquettaire
WO1992013552A1 (fr) * 1991-02-05 1992-08-20 Smithkline Beecham Corporation Peptides inhibant l'aggregation et contenant un amide ou un ester aromatique
WO1992017196A1 (fr) * 1991-03-28 1992-10-15 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques
WO1992018117A1 (fr) * 1991-04-11 1992-10-29 Rhone-Poulenc Rorer International (Holdings), Inc. Derives peptidiques et pseudopeptidiques antithrombotiques
WO1993018058A1 (fr) * 1992-03-06 1993-09-16 G.D. Searle & Co. Imitateurs peptidiques utiles comme inhibiteurs de l'agregation plaquettaire

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US4208430A (en) * 1979-03-15 1980-06-17 Smithkline Corporation Pharmaceutical compositions and method of inhibiting phenylethanolamine N-methyltransferase
US4672066A (en) * 1985-04-22 1987-06-09 Hoffmann-La Roche Inc. Derivatives of 4-acetyl-3-hydroxy-2-alkyl-phenoxycarboxylic acids
US4874864A (en) * 1988-05-24 1989-10-17 Pfizer Inc. Benzamide protease inhibitors

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EP0381033A1 (fr) * 1989-01-31 1990-08-08 F. Hoffmann-La Roche Ag Amides d'acides carboxyliques et amides sulfoniques
EP0445796A2 (fr) * 1990-03-09 1991-09-11 F. Hoffmann-La Roche Ag Dérivés de l'acide acétique
EP0454651A2 (fr) * 1990-04-23 1991-10-30 Monsanto Company Inhibiteurs de l'aggrégation plaquettaire
WO1992013552A1 (fr) * 1991-02-05 1992-08-20 Smithkline Beecham Corporation Peptides inhibant l'aggregation et contenant un amide ou un ester aromatique
WO1992017196A1 (fr) * 1991-03-28 1992-10-15 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques
WO1992018117A1 (fr) * 1991-04-11 1992-10-29 Rhone-Poulenc Rorer International (Holdings), Inc. Derives peptidiques et pseudopeptidiques antithrombotiques
WO1993018058A1 (fr) * 1992-03-06 1993-09-16 G.D. Searle & Co. Imitateurs peptidiques utiles comme inhibiteurs de l'agregation plaquettaire

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See also references of WO9414775A1 *

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EP0677043A4 (fr) 1995-11-22
US5726192A (en) 1998-03-10
JPH08505846A (ja) 1996-06-25
WO1994014775A1 (fr) 1994-07-07

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